EP0300111A1 - Feuchtigkeitsstabile feste Valproinsäure-Zubereitung und Verfahren zu ihrer Herstellung - Google Patents

Feuchtigkeitsstabile feste Valproinsäure-Zubereitung und Verfahren zu ihrer Herstellung Download PDF

Info

Publication number: EP0300111A1
Authority: EP; European Patent Office
Prior art keywords: weight percent; valproic acid; formulation; group; disintegrant
Prior art date: 1987-07-22
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP87810611A

Other languages

English (en)

French (fr)

Other versions

EP0300111B1 (de

Inventor

Aracelis M. Dr. Ortega

Pilar Martin Dr. De Perez

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Farvalsa AG

Original Assignee

Farvalsa AG

Farval AG

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1987-07-22

Filing date

1987-10-23

Publication date

1989-01-25

1987-10-23 Application filed by Farvalsa AG, Farval AG filed Critical Farvalsa AG

1987-10-23 Priority to AT87810611T priority Critical patent/ATE68346T1/de

1989-01-25 Publication of EP0300111A1 publication Critical patent/EP0300111A1/de

1991-10-16 Application granted granted Critical

1991-10-16 Publication of EP0300111B1 publication Critical patent/EP0300111B1/de

Status Expired legal-status Critical Current

Links

NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 47
229960000604 valproic acid Drugs 0.000 title claims abstract description 40
239000000203 mixture Substances 0.000 title claims abstract description 34
238000009472 formulation Methods 0.000 title claims abstract description 28
239000007787 solid Substances 0.000 title claims abstract description 7
238000000034 method Methods 0.000 title claims description 3
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 20
229920002261 Corn starch Polymers 0.000 claims abstract description 12
239000008120 corn starch Substances 0.000 claims abstract description 12
239000007884 disintegrant Substances 0.000 claims abstract description 12
239000011230 binding agent Substances 0.000 claims abstract description 11
239000000945 filler Substances 0.000 claims abstract description 11
239000000314 lubricant Substances 0.000 claims abstract description 11
239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 11
235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 11
239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 10
239000000395 magnesium oxide Substances 0.000 claims abstract description 10
CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 10
235000019359 magnesium stearate Nutrition 0.000 claims abstract description 10
AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims abstract description 10
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 9
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 9
229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 8
MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims description 36
238000002156 mixing Methods 0.000 claims description 10
PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 6
239000008187 granular material Substances 0.000 claims description 5
239000000463 material Substances 0.000 claims description 5
235000014113 dietary fatty acids Nutrition 0.000 claims description 4
239000000194 fatty acid Substances 0.000 claims description 4
229930195729 fatty acid Natural products 0.000 claims description 4
150000004665 fatty acids Chemical class 0.000 claims description 4
229920001592 potato starch Polymers 0.000 claims description 4
150000003839 salts Chemical class 0.000 claims description 4
229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
239000000454 talc Substances 0.000 claims description 4
229910052623 talc Inorganic materials 0.000 claims description 4
235000012222 talc Nutrition 0.000 claims description 4
CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
235000013539 calcium stearate Nutrition 0.000 claims description 3
239000008116 calcium stearate Substances 0.000 claims description 3
239000000843 powder Substances 0.000 claims description 3
239000011787 zinc oxide Substances 0.000 claims description 3
230000001476 alcoholic effect Effects 0.000 claims description 2
229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims description 2
235000012211 aluminium silicate Nutrition 0.000 claims description 2
229910000323 aluminium silicate Inorganic materials 0.000 claims description 2
229910021486 amorphous silicon dioxide Inorganic materials 0.000 claims description 2
BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 2
239000000292 calcium oxide Substances 0.000 claims description 2
ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 2
239000001913 cellulose Substances 0.000 claims description 2
229920002678 cellulose Polymers 0.000 claims description 2
150000004676 glycans Chemical class 0.000 claims description 2
239000000391 magnesium silicate Substances 0.000 claims description 2
235000012243 magnesium silicates Nutrition 0.000 claims description 2
229910044991 metal oxide Inorganic materials 0.000 claims description 2
150000004706 metal oxides Chemical class 0.000 claims description 2
229920000642 polymer Polymers 0.000 claims description 2
239000005017 polysaccharide Substances 0.000 claims description 2
239000002904 solvent Substances 0.000 claims description 2
239000000230 xanthan gum Substances 0.000 claims description 2
235000010493 xanthan gum Nutrition 0.000 claims description 2
229920001285 xanthan gum Polymers 0.000 claims description 2
229940082509 xanthan gum Drugs 0.000 claims description 2
238000001035 drying Methods 0.000 claims 2
FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
238000013329 compounding Methods 0.000 claims 1
229920001282 polysaccharide Polymers 0.000 claims 1
238000004513 sizing Methods 0.000 claims 1
229920003169 water-soluble polymer Polymers 0.000 claims 1
235000014692 zinc oxide Nutrition 0.000 claims 1
239000003826 tablet Substances 0.000 description 17
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
235000019441 ethanol Nutrition 0.000 description 6
229960004756 ethanol Drugs 0.000 description 6
238000005469 granulation Methods 0.000 description 5
230000003179 granulation Effects 0.000 description 5
239000002775 capsule Substances 0.000 description 4
239000007788 liquid Substances 0.000 description 4
238000004519 manufacturing process Methods 0.000 description 3
239000011253 protective coating Substances 0.000 description 3
AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 3
229940084026 sodium valproate Drugs 0.000 description 3
239000001961 anticonvulsive agent Substances 0.000 description 2
230000036765 blood level Effects 0.000 description 2
150000001875 compounds Chemical class 0.000 description 2
239000002662 enteric coated tablet Substances 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
235000019589 hardness Nutrition 0.000 description 2
159000000000 sodium salts Chemical class 0.000 description 2
239000006188 syrup Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
229940110185 valproic acid 500 mg Drugs 0.000 description 2
229920001353 Dextrin Polymers 0.000 description 1
239000004375 Dextrin Substances 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
239000002253 acid Substances 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
230000001773 anti-convulsant effect Effects 0.000 description 1
230000003556 anti-epileptic effect Effects 0.000 description 1
229940125681 anticonvulsant agent Drugs 0.000 description 1
229960003965 antiepileptics Drugs 0.000 description 1
238000003556 assay Methods 0.000 description 1
239000013060 biological fluid Substances 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
229940087373 calcium oxide Drugs 0.000 description 1
235000012255 calcium oxide Nutrition 0.000 description 1
159000000007 calcium salts Chemical class 0.000 description 1
229940078456 calcium stearate Drugs 0.000 description 1
229940095670 calcium valproate Drugs 0.000 description 1
PIZHURYFCSGTJX-UHFFFAOYSA-L calcium;2-propylpentanoate Chemical compound [Ca+2].CCCC(C([O-])=O)CCC.CCCC(C([O-])=O)CCC PIZHURYFCSGTJX-UHFFFAOYSA-L 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
229940105329 carboxymethylcellulose Drugs 0.000 description 1
239000007910 chewable tablet Substances 0.000 description 1
229940068682 chewable tablet Drugs 0.000 description 1
229940000425 combination drug Drugs 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
235000019425 dextrin Nutrition 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
239000000499 gel Substances 0.000 description 1
238000003018 immunoassay Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000012669 liquid formulation Substances 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
239000001923 methylcellulose Substances 0.000 description 1
235000010981 methylcellulose Nutrition 0.000 description 1
239000006186 oral dosage form Substances 0.000 description 1
238000004806 packaging method and process Methods 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
150000004804 polysaccharides Polymers 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
239000011369 resultant mixture Substances 0.000 description 1
239000000523 sample Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
239000007909 solid dosage form Substances 0.000 description 1
239000007892 solid unit dosage form Substances 0.000 description 1
238000012430 stability testing Methods 0.000 description 1
238000003756 stirring Methods 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
239000000126 substance Substances 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
238000011282 treatment Methods 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients

Definitions

This invention relates to the formulation of valproic acid, which is a liquid, into solid pharmaceutical form, in particular tablets.
the formulations of the invention provide valproic acid in a solid, moisture stable form without resort to protective coatings.
Valproic acid or its salts have known utility as anticonvulsants. However, a number of problems are associated with formulating them in solid form.
Valproic acid is disclosed in US-A-3,325,361. According to the Merck Index it is a liquid having anticonvulsant and antiepileptic activity. As a liquid it suffers from the difficulty attendant any liquid formulation; that is, it is inconvenient to use since the precise volume necessary to result in administration of the proper dose must be measured for each administration and it is less easily portable than solid dosage forms.
the present invention provides valproic acid as a moisture stable, solid formulation capable of being compressed into tablets.
valproic acid can be formulated into a dry, non-hydroscopic powder.
the powder is suitable for use in forming compacted tablets or for filling capsules. No protective coatings or other special packaging or protective measures are required to maintain the stability of the formulation against moisture.
the invention relates to a moisture stable valproic acid formulation comprising:
Fillers useful in the invention include alkaline earth metal oxides such as magnesium oxide and calcium oxide, earth metal oxides such as aluminium oxide, zinc oxide, clays such as magnesium silicates and aluminium silicates, and amorphous silicon dioxide.
the preferred filler is magnesium oxide. It is preferred that the filler be present at a 15 to 20 weight percent level.
Disintegrants are present in the formulation to facilitate disintegration in the stomach.
Polysaccharides such as corn starch, potato starch, dextrins and sugars, which swell thereby promoting disintegration are preferred.
Preferred disintegrants are corn starch or potato starch, preferably at levels of 10 to 20 weight percent. Corn starch at a level of 15 weight percent is most preferred.
Binders used in the formulation are preferably water soluble hydrophilic gel forming polymers.
Hydrophilic cellulose gums such as methylcellulose and carboxymethylcellulose, polyvinylpyrrolidone and xanthan gum are suitable binders.
the preferred binder is a combination of polyvinylpyrrolidone and sodium carboxymethylcellulose. These compounds are preferably combined in a 3:1 ratio, and the combination is preferably present in the formulation at a level of 3 to 6 weight percent.
Lubricants which are useful include talc, preferably talc USP, fatty acids such as stearic and salts of fatty acids such as magnesium stearate and calcium stearate.
talc preferably talc USP
fatty acids such as stearic
salts of fatty acids such as magnesium stearate and calcium stearate.
the lubricants are used at a level of 0.5 to 1.2 weight percent.
the most preferred lubricant is magnesium stearate at a level of 1 weight percent.
the most preferred formulation comprises:
the formulations are prepared as follows: Valproic acid is mixed with a solvent, preferably ethyl alcohol. The filler is slowly added with mixing and the resulting mass is dried and then milled. The disintegrant is then added with mixing. The resulting mixture is wet granulated with an alcoholic solution of the binder. The granules are dried and sized. Lubricants, optionally along with additional disintegrant and/or binder, are then mixed with the dried granules. The resultant lubricated mixture may be compressed into tablets or placed in capsules in amounts appropriate to a unit dosage - commonly 500 mg or less per tablet or capsule.
the preferred formulation set forth above may be made as follows.
the ingredients are used in the following proportions by weight: valproic acid, 500 parts; magnesium oxide, 140 parts; ethyl alcohol, 100 parts; corn starch, 122 parts; polyvinylpyrrolidone, 25 parts; sodium carboxymethylcellulose, 5 parts; and magnesium stearate, 5 parts.
the valproic acid is mixed with the ethyl alcohol (optimally in a 5:1 ratio).
the magnesium oxide is added slowly while stirring, preferably with a planetary mixer.
the wet mass produced is dried, for example, at 50°C in an oven for 16 hours.
the dried material is milled, preferably by means of a mesh screen, most preferably a 16 or 32 mesh screen.
the corn starch is added with mixing, preferably by means of a high shear mixer.
the mixture is wet granulated with 25% polyvinylpyrrolidone solution in ethyl alcohol.
the granules are dried, by way of example, in an oven at 60°C for 10 to 12 hours.
the dried granules are sized, preferably by means of a 16 mesh screen.
the sodium carboxymethylcellulose and magnesium stearate, optimally with some corn starch, are added and mixed, for example in a V-blender for ten minutes.
the resulting lubricated granulation can be formed into stable solid unit dosage forms.
the granulation can be placed in gelatin capsules or it can be compacted into tablets.
the amount of material used in each tablet or capsule is dependent on the dosage desired.
unit dosage forms contain 500 mg or less per tablet. Dosage levels and schedules would be in accordance with known practice.
the formulation is moisture stable and needs no protective coating
Mesh data are ASTM mesh.
the resulting lubricated granulation was compressed using a conventional tablet press to a tablet hardness within the range of 6 to 8 gk (Scheleuniger hardness tester).
the foregoing batch provides one hundred thousand 250 mg or fifty thousand 500 mg valproic acid tablets.
the granulation can be filled into hard gelatin capsules in the alternative.
Tablets manufactured in accordance with Example 1 were stability tested at drastic and normal temperature and humidity conditions.
the tablets were packaged in PVC blisters and then stored under three different conditions 45°C dry oven 37°C and 75% R.H. 25°C - 28°C (room temperature) Periodically the tablets were tested for physical appearance, physico-chemical properties and valproic acid content.
the following table shows the valproic acid content as percentage of the amount given on the label after storage for 6 months in drastic conditions and for three years at room temperature: Time (months) 45°C 37°C/75% R.H. Room Temperature 0 100.0 100.0 100.0 3 100.0 99.2 100.1 6 95.6 95.3 100.5 12 - - 97.3 24 - - 97.6 36 - - 97.2
the tablets disintegration time upon stability testing was as follows: Disintegration time (minutes) Time (months) 45°C 37°C/75% R.H. Room Temperature 0 25 25 25 3 35 35 25 6 35 35 25 12 - - 26 24 - - 25 36 - - 20
Valproic acid 500 mg tablets prepared according to Example 1 were tested for bioavailability in a randomized, 3-period cross-over study, using valproic acid syrup as a control and comparing with commercially available sodium valproate enteric coated tablets.
Valproic acid plasma concentrations were determined by E.M.I.T. assay method (a homogeneous enzyme immunoassay commonly used to measure valproic acid concentration in biological fluids).

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Inorganic Chemistry (AREA)
Medicinal Preparation (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

EP87810611A 1987-07-22 1987-10-23 Feuchtigkeitsstabile feste Valproinsäure-Zubereitung und Verfahren zu ihrer Herstellung Expired EP0300111B1 (de)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
AT87810611T ATE68346T1 (de)	1987-07-22	1987-10-23	Feuchtigkeitsstabile feste valproinsaeurezubereitung und verfahren zu ihrer herstellung.

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US7663487A	1987-07-22	1987-07-22
US76634		1987-07-22

Publications (2)

Publication Number	Publication Date
EP0300111A1 true EP0300111A1 (de)	1989-01-25
EP0300111B1 EP0300111B1 (de)	1991-10-16

Family

ID=22133265

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP87810611A Expired EP0300111B1 (de)	1987-07-22	1987-10-23	Feuchtigkeitsstabile feste Valproinsäure-Zubereitung und Verfahren zu ihrer Herstellung

Country Status (6)

Country	Link
US (1)	US5049586A (de)
EP (1)	EP0300111B1 (de)
AT (1)	ATE68346T1 (de)
DE (1)	DE3773926D1 (de)
ES (1)	ES2026198T3 (de)
GR (1)	GR3003187T3 (de)

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US5698226A (en) *	1993-07-13	1997-12-16	Glaxo Wellcome Inc.	Water-dispersible tablets
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1987
- 1987-10-23 AT AT87810611T patent/ATE68346T1/de not_active IP Right Cessation
- 1987-10-23 DE DE8787810611T patent/DE3773926D1/de not_active Expired - Fee Related
- 1987-10-23 ES ES198787810611T patent/ES2026198T3/es not_active Expired - Lifetime
- 1987-10-23 EP EP87810611A patent/EP0300111B1/de not_active Expired
1990
- 1990-05-02 US US07/517,620 patent/US5049586A/en not_active Expired - Fee Related
1991
- 1991-11-25 GR GR91401648T patent/GR3003187T3/el unknown

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Publication number	Priority date	Publication date	Assignee	Title
GR890100379A (el) *	1989-06-08	1991-11-15	Squibb & Sons Inc	Φαρμακευτικές συνθέσεις έχοντας καλή σταθερότητα.
CN1063971C (zh) *	1997-09-24	2001-04-04	中国兽药监察所	一种动物用冻干活疫苗制造方法

Also Published As

Publication number	Publication date
ES2026198T3 (es)	1992-04-16
GR3003187T3 (en)	1993-02-17
ATE68346T1 (de)	1991-11-15
EP0300111B1 (de)	1991-10-16
US5049586A (en)	1991-09-17
DE3773926D1 (de)	1991-11-21

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EP0300111A1 - Feuchtigkeitsstabile feste Valproinsäure-Zubereitung und Verfahren zu ihrer Herstellung - Google Patents

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